| Staff Listings |
Dr Sheena McGowan
ARC Future Fellow
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Tel: +61-3-9902 9309
Fax: +61-3-9902 9500
Office: Room 227, Level 2, Building 77
Email: sheena.mcgowan@monash.edu
The McGowan laboratory is interested in characterising novel molecular drug targets. The lab has a strong research focus in the design of novel anti-malarial drugs as well as other parasitic and bacterial diseases. Primarily we are a structural biology laboratory using techniques in X-ray crystallography, biochemistry and biophysics to analyse our proteins of interest. We use this mechanistic information to design inhibitors or analogues with potential applications in human medicine.
Sheena McGowan was formally trained in Microbiology, completing her PhD in 2004. During her PhD she studied the structure and function of a toxin regulator from the causative agent of gas gangrene, developing what would become a long-standing interest in structure and function of proteins. During her post-doctoral work she was trained in protein crystallography and biophysics and she now applies these skills in Microbiology and Structural Biology to investigate novel methods for microbial disease control.
Current Research Projects
Malaria
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Malaria is caused by infection of the protozoan parasites of the genus Plasmodium. The complex life-cycle of these parasites involves a reproductive cycle within host erythrocytes which is the cause of the clinical symptoms of malaria. During this blood stage, the parasites digest hemoglobin, a process critical for parasite survival. The final stage of this process is reliant on the activity of three metalloaminopeptidase enzymes, M1, M17 and M18. The absolute requirement of parasites to use aminopeptidase activity to digest host haemoglobin makes this process an ideal target for chemotheraputic intervention strategies and the three enzymes attractive targets for future antimalarials.
The three enzymes are thought to work in concert to facilitate protein turnover however the mechanism by which each protease modulates and controls hydrolysis remains to be elucidated. Each enzyme must regulate substrate size, specificity and active site access to prevent uncontrolled hydrolysis. A detailed understanding of this mechanism of action and control will be vital if we are to design inhibitors that can mimic the natural substrate entry and block the active site of these enzymes. The high-resolution X-ray crystal structures of the M1 and M17 enzymes have been determined by our laboratory. However further knowledge of the mechanisms of action and regulation, in combination with a detailed atomic knowledge of the active sites and quarternary structures, will be essential not only to future anti-malarial drug design projects but also our fundamental basic understanding of these important enzymes.
Collaborators in these projects include:
Drs. Donald Gardiner and Katharine Trenholme (Queensland Institute of Medical Research)
Prof John Dalton (McGill University, Canada)
Prof James Whisstock (Monash University)
A/Prof Doron Greenbaum (University of Pennsylvania, USA)
A/Prof Marcin Drag (Wroclaw University Technology, Poland)
Toxoplasmosis
Toxoplasmosis is a parasitic disease caused by the protozoan parasite Toxoplasma gondii. The disease rarely causes symptoms in healthy adults however in immunocompromised patients and pregnant women the disease can be fatal and/or cause serious developmental defects in the fetus. In collaboration with Prof Vern Carruthers (University of Michigan, USA) we are performing structural and functional studies on the M16A metalloprotease from Toxoplasma gondii. This protease, also known as TLN4, has been shown to have a role in host cell invasion and parasite development.
Pseudomembraneous colitis
Pseudomembranous colitis is an infection of the large intestine with an overgrowth of Clostridium difficile. It is the major cause of hospital associated diarrhoea in the developed world and is estimated to cost the US health care system ~ $3.2 billion / year. The disease is caused by large toxins produced by the C. difficile bacteria. In collaboration with Dr. Dena Lyras (Monash University) we study a novel toxin regulator found within the C. difficile proteome with the aim to determine the mechanism of regulation of toxin production.
Streptococcal Infections
p>Infection with the Streptococcus pyogenes bacteria can result in "strep throat" and scarlet fever. Bacteriophage lysins are peptidoglycan hydrolases that act to lyse the bacterial host cell wall. We are currently investigating a novel and potent lysin that targets S. pyogenes. In collaboration with Prof Vince Fischetti (Rockefeller University, USA); A/Prof Dan Nelson (University of Maryland, USA); Prof James Whisstock (Monash University) and A/Prof Ashley Buckle (Monash University), we aim to develop this enzyme as novel anti-bacterial agent or ‘enzybiotic'. |
Marine Venoms
The Australian "box jellyfish" or Chironex fleckeri is arguably the most venomous creature in the world. In collaboration with A/Prof Wayne Hodgson (Monash Venom Group); Dr. Geoff Isbister (University of Newcastle) & Dr. Jamie Seymour (James Cook University we are studying the structure and function of key lethal protein factors from the box jellyfish. This will aid with current treatments of envenomed patients as well as future pharmacology targets.
Opportunities to join the lab
Honours and PhD Projects are currently available in the laboratory. The lab uses a wide range of molecular and structural biology techniques to study the mechanism and function of target proteins. If you are interested in any of the research occurring in the laboratory, please feel free to contact Sheena anytime.
For more information about studying an Honours degree at Monash University click here:
http://www.med.monash.edu.au/biochem/teaching/hons-general.html
For more information about studying a Masters / PhD degree at Monash University click here:
http://www.med.monash.edu.au/biochem/phd/
The Facilities
The laboratory is located within the new ‘Science & Technology Research & Innovation Precinct' that brings together a diverse cross-section of research teams and high-tech industries from within the Monash University School of Biomedical Sciences. This biomedical research hub located on the Clayton campus, now known simply as the ‘STRIP' is one of the largest biomedical precincts in Australia. With an investment of over $280 million, 700 research staff and over 270 PhD students are located in the new buildings with the latest facilities and equipment to expand their research.
Monash University is recognized as one of the leading structural biology units in Australia, with ten independent structural biology laboratories, a new $5 million Grollo Ruzzene Foundation Centre for Protein Structure with state-of-the-art crystallisation robotics, crystallisation imaging technology and in-house data collection facilities, a dedicated protein production facility, a 800-core Apple supercompute cluster dedicated to structural biology - all of which are located with walking distance to the Australian Synchrotron.
Recent Publications
G. Velmourougane, M. B. Harbut, S. Dalal, S. McGowan, C.A. Oellig, N. Meinhardt, J.C. Whisstock, M. Klemba, D.C. Greenbaum. (2011) Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the s1 pocket of the essential malaria M1 metalloaminopeptidase. J Med Chem 54(6): 1655-66.
*S. McGowan, C.A. Oellig, Birru, W.A., Caradoc-Davies, T.T., C.M. Stack, J. Lowther, T.S. Skinner-Adams, A. Mucha, P. Kafarski, J. Grembecka, K.R. Trenholme, A.M. Buckle, D.L. Gardiner, J.P. Dalton. & J.C. Whisstock (2010) Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral aminopeptidases. Proc. Nat. Acad. Sci. U.S.A. 107(6): 2449-2454.
*S. McGowan, *C.J. Porter, *J. Lowther, C.M. Stack, S.J. Golding, T.S. Skinner-Adams, K.R. Trenholme, F. Teuscher, S.M. Donnelly, J. Grembecka, A. Mucha, P. Kafarski, R. DeGori, A.M. Buckle, D.L. Gardiner, J.C. Whisstock & J.P. Dalton. (2009) Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase: a new route for antimalarial compounds. Proc. Nat. Acad. Sci. U.S.A. 106(8): 2537-2542
T.S. Skinner-Adams, C.M. Stack, K.R. Trenholme, C.L. Brown, J. Grembecka, J. Lowther, A. Mucha, M. Drag, P. Kafarski, S. McGowan, J.C. Whisstock, D.L. Gardiner & J.P. Dalton. (2009) Plasmodium falciparum neutral aminopeptidases: new targets for anti-malarials. (2010) TiBS., 35(1): 53-61 (Journal Cover illustration)
K L. Winter, G.K. Isbister, S. McGowan, N. Konstantakopoulos, J.E. Seymour & W.C. Hodgson. (2010) A pharmacological and biochemical examination of the geographical variation of Chironex fleckeri venom. Tox Letters 192: 419-424.
